The broad, long-term objective of the proposed research is to determine if alterations in base excision repair (BER) genes that exist in the normal population and in tumors lead to phenotypes that could be linked to the etiology of cancer or to treatment response. The specific aims of the application are to test the hypothesis that polymorphisms in BER genes lead to cellular transformation, to test the hypothesis that BER variants arising in the normal population and in tumors lead to genomic instability, and to test the hypothesis that BER protein variants affect cancer treatment. To test these hypotheses we will take a combined genetic and biochemical approach. We will express the variant BER proteins in cells and determine whether they induce focus formation, anchorage independent growth, and tumors in mice. We will determine if expression of the variants in cells induces mutations, and characterizethe types of mutations they induce. We will determine if the variants are differentially sensitive to various cancer treatments, including ionizing radiation and alkylating agents, the latter in collaboration with Project 1. We will also characterize the drug sensitivity of cells in which multiple DMA repair pathways are compromised, in collaboration with Projects 1, 2, and 4. This proposal has the potential to further our understanding of the relationship between BER variants and cancer etiology, and to provide mechanistic insights into the role of aberrant BER in cancer onset and treatment. Because BER is responsible for the repair of 10,000 lesions per cell per day and is a highly coordinated process, we suspect that even minor imbalances in this system will impact cancer etiology. A thorough understanding of BER variants in people will also serve as the basis for a future study of environmental aspects of cancer promotion and progression within the context of these BER variants and has the potential to provide important insight on lifestyle choices regarding cancer prevention.